Antibiotic resistance: Researchers have directly proven that bacteria can change shape inside humans to avoid antibiotics

Antibiotic resistance poses one of the biggest threats to global public health.

bacteria like e coli can change shape to resist antibiotics
Sean Gallup/Getty Images

Widespread antibiotic use is largely to blame for the emergence of antibiotic resistant bacteria, which is currently one of the biggest threats to global health.


Not only does antibiotic resistance already cause an estimated 700,000 deaths a year, it's also made numerous infections, including pneumonia, tuberculosis, and gonorrhoea, harder to treat. Without knowing how to stop bacteria from developing antibiotic resistance, it's predicted that preventable diseases could cause 10m deaths a year by 2050.

Some of the ways that bacteria become resistant to antibiotics is through changes in the bacteria's genome. For example, bacteria can pump the antibiotics out, or they can break the antibiotics down. They can also stop growing and divide, which makes them difficult to spot for the immune system.

However, our research has focused on another little known method that bacteria use to become antibiotic resistant. We have directly shown that bacteria can “change shape" in the human body to avoid being targeted by antibiotics – a process that requires no genetic changes for the bacteria to continue growing.

Virtually all bacteria are surrounded by a structure called the cell wall. The wall is like a thick jacket which protects against environmental stresses and prevents the cell from bursting. It gives bacteria a regular shape (for example, a rod or a sphere), and helps them divide efficiently.

Human cells don't possess a cell wall (or “jacket"). Because of this, it's easy for the human immune system to recognise bacteria as an enemy because its cell wall is noticeably different. And, because the cell wall exists in bacteria but not in humans, it's an excellent target for some of our best and most commonly used antibiotics, such as penicillin. In other words, antibiotics targeting the wall can kill bacteria without harming us.

However, bacteria can occasionally survive without their cell wall. If the surrounding conditions are able to protect the bacteria from bursting, they can turn into so-called “L-forms", which are bacteria that don't have a cell wall. These bacteria were discovered in 1935 by Emmy Klieneberger-Nobel, who named them after the Lister Institute where she was working at the time.

In a lab, we often use sugar to create a suitably protective environment. In the human body, this change in form is typically triggered by antibiotics that target the bacteria's cell wall, or certain immune molecules – such as lysozyme, a molecule that's present in our tears which helps protect us from bacterial infections.

Bacteria without a cell wall often become fragile and lose their regular shape. However, they also become partially invisible to our immune system, and completely resistant to all types of antibiotics that specifically target the cell wall.

Scientists long suspected that L-form switching might contribute to recurrent infections by helping bacteria hide from the immune system and resist the antibiotics. However, it was difficult to find evidence for this theory due to the elusive nature of L-forms and lack of appropriate methods to detect them.

Watching bacteria change shape

Our study, published in Nature Communications, looked specifically at bacterial species associated with recurrent urinary tracts infections (UTIs). It found that many different bacterial species – including E. coli and Enterococcus – can indeed survive as L-forms in the human body. This is something that has never been directly proven before. We were able to detect these sneaky bacteria using fluorescent probes that recognise bacterial DNA.

We tested urine samples from elderly patients with recurrent UTIs by growing them in a petri dish high in sugars. Not only did this environment help protect bacteria from bursting, it also isolated the L-form bacteria that were present in these samples. In a separate experiment, we were able to see the whole process take place in living zebrafish embryos in the presence of antibiotics.

After the antibiotic was removed, the bacteria transformed back from L-forms to their regular form with cell walls. (Credit to Newcastle University, UK)

Importantly, our study shows that antibiotics need to be tested in conditions more reflective of the human body. The ones that are currently used in the medical laboratory don't provide enough protection for delicate L-forms to survive.

Before we can fully understand how important L-form switching is compared to other forms of antibiotic resistance, further research using more patients will be needed. It will also be important to investigate what role L-forms may play in other recurrent infections, such as sepsis or pulmonary infections.

Until now, research into L-forms has been a controversial field, but our hope is that these findings will motivate more research into L-forms in disease situations. Our hope is that these findings will help find a way to clear these sneaky bacteria from our body. Combining cell wall active antibiotics with ones that would kill L-forms might be one solution of fighting antibiotic resistant infections.

Our battle with bacteria is ongoing. As we come up with new strategies to fight them, they come up with ways to fight back. Our study highlights yet another way that bacteria adapt that we'll need to take into account in our continuing battle with infectious disease.The Conversation

Katarzyna Mickiewicz, Newcastle University Research Fellow, Newcastle University.

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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This article was originally published by our sister site, Freethink.

For the first time, researchers appear to have effectively treated a genetic disorder by directly injecting a CRISPR therapy into patients' bloodstreams — overcoming one of the biggest hurdles to curing diseases with the gene editing technology.

The therapy appears to be astonishingly effective, editing nearly every cell in the liver to stop a disease-causing mutation.

The challenge: CRISPR gives us the ability to correct genetic mutations, and given that such mutations are responsible for more than 6,000 human diseases, the tech has the potential to dramatically improve human health.

One way to use CRISPR to treat diseases is to remove affected cells from a patient, edit out the mutation in the lab, and place the cells back in the body to replicate — that's how one team functionally cured people with the blood disorder sickle cell anemia, editing and then infusing bone marrow cells.

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Another option is to insert the CRISPR system itself into the body so that it can make edits directly in the affected organs (that's only been attempted once, in an ongoing study in which people had a CRISPR therapy injected into their eyes to treat a rare vision disorder).

Injecting a CRISPR therapy right into the bloodstream has been a problem, though, because the therapy has to find the right cells to edit. An inherited mutation will be in the DNA of every cell of your body, but if it only causes disease in the liver, you don't want your therapy being used up in the pancreas or kidneys.

A new CRISPR therapy: Now, researchers from Intellia Therapeutics and Regeneron Pharmaceuticals have demonstrated for the first time that a CRISPR therapy delivered into the bloodstream can travel to desired tissues to make edits.

We can overcome one of the biggest challenges with applying CRISPR clinically.

—JENNIFER DOUDNA

"This is a major milestone for patients," Jennifer Doudna, co-developer of CRISPR, who wasn't involved in the trial, told NPR.

"While these are early data, they show us that we can overcome one of the biggest challenges with applying CRISPR clinically so far, which is being able to deliver it systemically and get it to the right place," she continued.

What they did: During a phase 1 clinical trial, Intellia researchers injected a CRISPR therapy dubbed NTLA-2001 into the bloodstreams of six people with a rare, potentially fatal genetic disorder called transthyretin amyloidosis.

The livers of people with transthyretin amyloidosis produce a destructive protein, and the CRISPR therapy was designed to target the gene that makes the protein and halt its production. After just one injection of NTLA-2001, the three patients given a higher dose saw their levels of the protein drop by 80% to 96%.

A better option: The CRISPR therapy produced only mild adverse effects and did lower the protein levels, but we don't know yet if the effect will be permanent. It'll also be a few months before we know if the therapy can alleviate the symptoms of transthyretin amyloidosis.

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If everything goes as hoped, though, NTLA-2001 could one day offer a better treatment option for transthyretin amyloidosis than a currently approved medication, patisiran, which only reduces toxic protein levels by 81% and must be injected regularly.

Looking ahead: Even more exciting than NTLA-2001's potential impact on transthyretin amyloidosis, though, is the knowledge that we may be able to use CRISPR injections to treat other genetic disorders that are difficult to target directly, such as heart or brain diseases.

"This is a wonderful day for the future of gene-editing as a medicine," Fyodor Urnov, a UC Berkeley professor of genetics, who wasn't involved in the trial, told NPR. "We as a species are watching this remarkable new show called: our gene-edited future."

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